1. Field of the Invention
The present invention relates generally to the field of automatic dissolution testing of products whose solubility and dissolution rate properties affect product performance, and more specifically to the optimal prediction of product dissolution characteristics using known product data as a reference for a feedback controlled apparatus.
The methods disclosed and the electronically controlled apparatus described are presented in connected with in vitro dissolution testing of pharmaceutical drug dosage forms to predict in vivo bioavailability. However, both the methods and apparatus taught are equally applicable to dissolution testing of agricultural products formulated as controlled release herbicides, insecticides, fertilizers, and the like; and are further applicable to the dissolution testing of components of industrial products including solid materials whose solubility properties depend on a wide variety of factors.
2. Description of the Prior Art
Dissolution testing of components of industrial products whose solubility and dissolution rate properties affect product performance can be used as a screening and quality control tool. The solubility properties of solid materials can depend on polymorphic crystalline form, crystal habit, crystal shape, particle size and particle size distribution, and state of solvation. A simple and rapidly performed dissolution test can substitute for the determination of these physical properties by more time consuming and expensive methods such as x-ray crystallography, differential thermal analysis, microscopy, etc. The materials are instead determined as to whether they conform to a dissolution rate standard under specified conditions and in relation to a known reference sample of the same material characterized by the above physical properties and possessing the desired dissolution rate and solubility characteristics.
The broad technique of determining dissolution rate properties is especially of interest in the testing of drug products where the therapeutic performance of drugs is closely related to the drug dissolution properties. Seemingly minor changes in drug product formulation, as well as the inadvertent variation in materials and manufacture that can occur between batches of the same product formulation, can influence the therapeutic performance of drugs. In vivo bioavailability testing of drug products in humans provides the most reliable means of ensuring bioequivalence. However, it is impractical to perform the extensive and expensive human testing that would be routinely required. Large numbers of human subjects would be placed at risk if such studies were conducted. Bioavailability testing in which humans are used as test subjects can be minimized by the development and implementation of in vitro dissolution standards that reflect in vivo drug-product performance. In vitro bioequivalence requirements have been established for some drugs such as digoxin. From among the various chemical and physical tests that can be performed on drug solids in vitro for correlating or predicting a drug product's in vivo bioavailability behavior, dissolution testing is the most sensitive and reliable. The correlative relationships most commonly reported between the vitro dissolution and in vivo bioavailability are of the single-point type: the percentage of the drug dissolved in a given time (or the time it takes to dissolve a given percentage of the drug in vitro) and some univariate characteristic of the drug product's in vivo response versus time profile (such as the peak blood level, the time required to reach the peak or 50% of the peak, or the area under the blood-level curves) are correlated. The selection of in vitro dissolution and in vivo bioavailability parameters for such single-point correlations is frequently arbitrary, and the results can be misleading. Obviously, it would be preferable to predict the entire average blood level, urinary recovery rate, pharmacological-response-time, or drug absorption rate vs. time profile that would be elicited by a drug product in a panel of human subjects rather than merely to correlate univariate characteristics of the dissolution profile with an in vivo bioavailability parameter. In all cases, however, the fidelity of the in vitro dissolution results in correlating and in predicting in vivo drug-product bioavailability depends upon the dissolution-test process variables, such as the dissolution-medium composition, the solubility volume of the medium (sink conditions that determine the extent to which the medium becomes saturated with the drug), and the agitation rates (stirring or flow rates). An improper choice of these process variables (e.g., an excessively high rate of agitation) can mask significant bioavailability differences among drug products. On the other hand, the dissolution test can be overly sensitive in detecting differences that are negligible in vivo. In the former case, using such improper dissolution-test parameters would result in the marketing of therapeutically ineffective drug products. In the latter case, the result would be the discarding of drug products that are entirely satisfactory in terms of in vivo performance. Serious economic losses could result from the use of an overly sensitive in vitro dissolution test for lot-to-lot reproducibility testing of drug products. Therefore, whether the dissolution test is being used as a quality control tool, as an in vivo bioequivalency requirement for multisource generic drug products, or as a substitute for human bioavailability testing during the development of new drug-product formulations, it is imperative that the dissolution test provide predictive results that are biologically relevant.
Developing drug-product dissolution tests that predict the time course of drug-product bioavailability can be fraught with pitfalls, some of which may be avoided through knowledge and consideration of the physiochemical properties of the components of the drug product and the biological processes and conditions operative in the release of the drug from the gastrointestinal tract and its subsequent absorption. However, it is not only futile, but also unnecessary to attempt to reproduce the complex of biological factors operating in vivo in the effort to develop a satisfactory in vitro bioavailability test, although such attempts have been made. The devices that resulted from these efforts are of value now only as museum pieces. It would, however, be imprudent to ignore such knowledge when it can be used advantageously to circumvent a problem in the design of a dissolution test.
There are two possible general approaches to developing in vivo relevant drug product dissolution tests. Both approaches seek to predict the entire time course of average blood levels that would be observed for a drug product in a panel of human test subjects. In this way, the dissolution test serves as a substitute for human testing.
The first approach is a computational method that maximizes the amount of information that can be obtained from conventional methods of in vitro dissolution testing. Used most frequently are the USP rotating-basket apparatus, the FDA paddle method, the stationary-basket/rotating filter apparatus, Sartorious solubility and absorption simulators (Sartorius, Incorporated, Hayward, Calif.), and column-type flow-through assemblies. The last of these devices offers advantages with regard to the definition, flexibility of control, standardization, and reproducibility of process variables. This apparatus has been used by the inventor of the present invention to demonstrate the second approach to predicting in vivo blood-level curves that emerge from the apparatus in the form of dissolution rate versus time profiles.
Since the computational approach with conventional apparatus depends upon the relatively arbitrary selection of process variables, its usefulness is limited. However, using feedback control to continuously vary the process variables, as described below, obviates this problem. For a more complete treatment of the mathematical (and theoretical) aspects of the dissolution, the interested reader is directed to three papers co-authored by the inventor. These are: V. F. Smolen et al., "Optimally Predictive In Vitro Drug Dissolution Testing for In Vivo Bioavailability," J. Pharmaceutical Sci., Vol. 65, No. 12, pp. 1718-1724, December 1976; V. F. Smolen et al., "Predicting the Time Course of In Vivo Bioavailability From In Vitro Dissolution Tests: Control Systems Engineering Approaches," Pharmaceutical Technology, pp. 89-102, June 1979; and V. F. Smolen et al., "Predictive Conversion of In-Vivo Drug Dissolution Data into In Vivo Drug Response Versus Time Profiles Exemplified for Warfarin," J. Pharmaceutical Sci., Vol. 66, No. 3, pp. 297-304, March 1977.
The present invention is directed to an improved method and apparatus for carrying out the dissolution approach to optimally predicting in vivo drug bioavailability from pharmaceutical dosage forms, and other applications of dissolution testing.